The present invention relates to methods for improving the therapeutic response of human patients with major depression, particularly those carrying the gene for apolipoprotein E4.
Psychiatric diseases generally provide a unique set of complications for clinicians, patients, and care givers. Major depression, for instance, is a major health problem and poses a tremendous financial burden on society due to lost self-support of individuals suffering from depression. Such individuals are often simply unable to function in everyday life situations, in part because of feelings of extreme hopelessness and worthlessness. There is also a serious risk of suicide among such individuals. The various forms of depression are defined and are separately diagnosed according to criteria given in handbooks for psychiatry, for example in the Diagnostic and Statistical Manual of Mental Disorders 4th edition (DSM-IV) published by the American Psychiatric Association, Washington, D.C. (1994). The diagnostic criteria for major depression are well known to those skilled in the art, and comprise the criteria set forth, for example, at DSM-IV 296.2 and 296.3. Major depression, defined in more detail below, is also known as major depressive disorder and is estimated to affect between 5 to 10% of the human population.
Although treatments for different types of depression do exist, there is a continuous search for new methods of treatment of depression because existing methods still have disadvantages, such as the side effects of drugs, the long duration of treatments, and, more importantly, the partial efficacy (or inefficacy) of treatments. For example, there is wide variation in the response of patients with major depression to antidepressant pharmacotherapy. Some of this variation may be due to genetic differences among patients. Regardless, the result is that about 30% of patients with major depression who are treated with existing antidepressant drugs do not improve.
Among the various drugs available for therapy of depression, there are groups of drugs with totally different mechanisms of action. Such mechanisms include, for example, the blockage of reuptake of serotonin; the blockage of reuptake of noradrenaline; or the blockage of presynaptic receptors on noradrenergic or serotonergic nerve terminals. Such different mechanisms of action make it possible to make conscious choices regarding treatments for depression based on different biochemical mechanisms. However, it has not been known which characteristics of a patient predict a better response to one particular kind of drug over another, so treatment choices have been complicated by the fact that it often takes a significant period of treatment to determine whether or not a drug is having a therapeutic effect or is merely slower in having its therapeutic effect.
Accordingly, treatment with the most effective drug(s) is often delayed while the disease continues to disrupt daily functioning of the patient. Even a patient who may ultimately improve after weeks or months of treatment with one drug may have improved much faster with another drug if only it had been tried sooner. Thus the failure to treat the disease in the most effective manner results in lessened quality of life for the patient not only in the immediate time frame but also in the foreseeable future.
Currently, the expanding field of pharmacogenetics would like to identify DNA markers for differential medication response, thereby using these markers to individualize patient treatment in order to maximize therapeutic response and minimize side effects. Thus, a method which would allow one to predict which patients will respond to specific therapeutics and dosages would provide physical and psychological benefits. Specifically, the efficacy of antidepressant treatment would be greatly improved if there were better methods available to identify the patients which would respond the fastest and with the best therapeutical benefit to a particular kind of treatment.
One characteristic that has been studied extensively with respect to Alzheimer""s Disease (AD) and possible treatments thereof is the gene for apolipoprotein E (apoE). The apoE gene on chromosome 19 has three common alleles (xcex52, xcex53, and xcex54), which encode three major apoE isoforms (E2, E3, and E4). The three alleles correspond to six genotypes, i.e., xcex52/xcex52, xcex52/xcex53, xcex52/xcex54, xcex53/xcex53, xcex53/xcex54, and xcex54/xcex54. In typical populations, for example, xcex53 is the most common allele, occurring on more than 75% of chromosomes. The average frequency of xcex52 is 8% and the average frequency of xcex54 is 15%. See, e.g., Farrer, L. A. et al., JAMA 278:1349-1356, 1997.
ApoE functions as a ligand in the process of receptor mediated internalization of lipid-rich lipoproteins, and it is probably also involved in reverse lipid transport. See, e.g., Mahley, R. W. et al., Biochem: Biophys. Acta. 737:197-222 (1983). In the central nervous system, apoE plays a central role in the mobilization and redistribution of cholesterol and phospholipid during membrane remodeling associated with synaptic plasticity. See, e.g., Poirier, J. et al., Mol. Brain. Res., 9:191-195 (1991); Poirier, J. et al., Mol. Brain. Res., 11:97-106 (1991); Poirier, J. et al., Neuroscience, 55:81-90(1993).
In view of the studies with Alzheimer""s disease, the apoE xcex54 allele has been found to be an established genetic risk factor for Alzheimer""s disease. See, e.g., Hirono, N. et al., J. Neuropsych. Clin. Neurosci. 11:66-70 (1999). In contrast, the art provides no evidence that the apoE xcex54 allele is a risk factor for major depression. See e.g., Mauricio, M. et al., Am. J. Geriatr. Psychiatr. 8:196-200 (2000); Forsell, Y. et al., Biol. Psychiatry 42: 898-903 (1997); Heidrich, A. et al., Biol. Psychiatry 41:912-914 (1997); Papassotiropoulos, A. et al., Dement. Geriatr. Cogn. Disord. 10:258-261 (1999); and Schmand, B. et al., Soc. Psychiatry Psychiatr. Epidemiol. 33: 21-26 (1998).
With respect to Alzheimer""s, although it is not determinative of the disease, it has been found that human patients carrying at least one apoE xcex54 allele have a much greater chance of developing the disease. See, e.g., Levy, M. et al., Biol. Psychiatry 45:422-425 (1999). In addition, the apoE xcex54 allele has been associated with cognitive deficits in nondemented elderly in a number of studies. See, e.g., O""Hara, R. et al., J. Am. Geriatr. Soc. 46:1493-1498, (1998). There are several reasons why nondemented elderly patients who suffer from mild cognitive impairment associated with carrying the apoE xcex54 allele may have been poorly responsive to certain antidepressant medication treatments. First, nondemented depressed subjects carrying the apoE xcex54 allele may have mild brain dysfunction rendering them unresponsive to the therapeutic neurochemical changes induced by antidepressant agents. Second, recovery from depression is currently thought to depend in part on a restructuring of cognition and behavior that maintains the depressed mood. Mild cognitive impairment in apoE xcex54 allele carriers may have made it difficult for these individuals to effect the cognitive changes necessary for recovery from depression. Finally, certain types of anti-depressant drugs, e.g., paroxetine, may negatively affect cognition, and subjects with the apoE xcex54 allele may be more vulnerable to such effects than subjects without the allele.
Thus, one would have expected carriers of the apoE xcex54 allele to be poor candidates for treatment of major depression.
Surprisingly, however, the inventors have found, as a result of clinical trials described herein, that for at least one antidepressant drug, mirtazapine, there are clear improvements in therapeutic response among patients with at least one apoE xcex54 allele as opposed to those without an apoE xcex54 allele. Specifically, mirtazapine has been found to be particularly effective as an antidepressant for apoE xcex54 carriers. This biochemical trait difference in depressed patients can be used to predict a faster and more effective therapeutic response to mirtazapine. In other words, the present inventive method may be used to identify depressed patients who are most likely to show a very good response to mirtazapine.
Mirtazapine is an antidepressant drug, known as a NaSSA (a Noradrenergic and Specific Serotonergic Antidepressant). Mirtazapine has been marketed for the treatment of major depression by Organon Inc. under the tradename REMERON(copyright). Mirtazapine is disclosed in U.S. Pat. No. 4,062,848, the disclosure of which is hereby incorporated by reference. Mirtazapine belongs to the piperazino-azepine group of compounds and is designated 1,2,3,4,10,14b-hexahydro-2-methylpyrazino[2,1-a]pyrido[2,3-c]benzazepine. Mirtazapine increases both noradronergic and serotonergic neurotransmission by blocking both central xcex12-adrenergic autoreceptors and xcex12-adrenergic heteroreceptors and selectively blocking the 5-HT2 and 5-HT3 receptors. See, e.g., de Boer, T., J. Clin. Psychiatry 57 suppl 4:19-25 (1996).
Thus, the present invention relates to methods for improving the therapeutic response of a human patient with major depression by administering mirtazapine, in an amount effective to treat major depression, to a human patient carrying the gene for apolipoprotein xcex54. The invention also relates to methods for improving the therapeutic response of human patients with major depression by determining the apolipoprotein E genotype of a human patient and then administering mirtazapine, in an amount effective to treat major depression, to those human patients who are found to carry the gene for apolipoprotein xcex54.
For purposes of the present invention, the following terms are defined:
xe2x80x9cAlzheimer""s Disease (AD)xe2x80x9d means a pathology characterized by an early and extensive loss of entorhinal cortex neurons, and by neuritic plaques and neurofibrillary tangles. AD patients may be identified by progressive and degenerative effects on the brain which cannot be attributed to causes other than AD.
xe2x80x9cDetermining the apolipoprotein (apoE) genotypexe2x80x9d means screening patients to determine the type and number of apoE alleles present in the patient. Such screening may be carried out by nucleic acid sequencing of DNA. For example, the screening may be accomplished by restriction isotyping methods, which include the general steps of polymerase chain reaction amplification, restriction digestion, and gel electrophoresis. Screening may also be carried out by other types of nucleic acid sequencing, e.g., by hybridization or oligotyping. Alternatively, the screening may involve examination of which apolipoprotein isoforms are present in the patient""s plasma, or xe2x80x9cphenotypingxe2x80x9d.
xe2x80x9cGene for apolipoprotein E (apoE gene)xe2x80x9d means the gene which encodes for the three major isoforms (apoE2, apoE3, and apoE4) of apolipoprotein E. The apoE gene on chromosome 19 has three common alleles (xcex52, xcex53, and xcex54) which correspond to the three isoforms apoE2, apoE3, and apoE4.
xe2x80x9cGene for apolipoprotein E4 (apoE4 gene)xe2x80x9d, means the gene which encodes for apoE4 via one of three genotypes: xcex52/4, xcex53/xcex54, and xcex54/xcex54. This term is used interchangeably herein with the term xe2x80x9capoE xcex54 allelexe2x80x9d, i.e., the specific allele that encodes for apoE4. The DNA and amino acid sequences of the apoE4 gene and of apoE4 itself are known and are available, e.g., at GenBank Accession No. M10065.
xe2x80x9cImproved therapeutic responsexe2x80x9d or xe2x80x9cimproving the therapeutic responsexe2x80x9d means a faster onset of antidepressant action of a particular drug treatment, and a better treatment result, e.g., in terms of reducing or eliminating the symptoms of depression.
xe2x80x9cMajor depressionxe2x80x9d or xe2x80x9cmajor depressive disorderxe2x80x9d is defined by the occurrene of at least one major depressive episode. Such an episode implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed or dysphoric mood that usually interferes with daily functioning, and includes at least five of the following nine symptoms: depressed mood, loss of interest in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt or suicidal ideation.
According to the present invention, the therapeutic response of a human patient with major depression is improved by administering mirtazapine, in an amount effective to treat major depression, to human patients carrying the gene for apoE4. In another embodiment of the invention, the therapeutic response of a human patient with major depression is improved by determining the apolipoprotein E genotype of a human patient and then administering mirtazapine, in an amount effective to treat major depression, to those patients who are found to carry the gene for apolipoprotein E4. As described above, the determination of apoE genotype is generally carried out either by phenotyping, e.g., analyzing apolipoprotein particles present in the patient""s plasma, or by nucleic acid sequencing of DNA, e.g., a polymerase chain reaction approach, such as restriction isotyping. ApoE and the genetic sequences of the various genotypes of the apoE gene, including those for apoE4, are discussed, e.g., in Mahley, R. W. et al., Biochem. Biophys. Acta. 737:197-222 (1983) and in Hixson et al., J. Lipid Res. 31:545-548 (1990).
The amount of mirtazapine effective to treat major depression will, of course, vary and is ultimately at the discretion of the medical practitioner. The factors to be considered include the route of administration and nature of the formulation, the body weight, age, and general state of health, and severity of the depression. Unless otherwise stated, all weights of active ingredients referred to herein are calculated in terms of the active drug per se. In general, a suitable dose of mirtazapine for administration to a human will be in the range of 5 to 100 mg per day. In one embodiment, the suitable dosage range for administration of mirtazapine to a human may be 15 to 45 mg per day, The desired dose may be presented as two, three, four, five, or more sub-doses administered at appropriate intervals throughout the day. These sub-doses may be administered in unit dosage forms, for example, containing 7.5 mg, 15 mg, or 30 mg, or any unit dosage useful to allow multiple dosing in a single day.
Unless otherwise indicated, all numbers expressing quantities, reaction conditions, and so forth used herein are to be understood as being modified in all instances by the term xe2x80x9cabout.xe2x80x9d Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification herein and in the attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.
Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.
Pharmaceutical formulations according to the present invention comprise mirtazapine together with at least one pharmaceutically acceptable carrier and optionally at least one other therapeutic agent. xe2x80x9cAcceptablexe2x80x9d means compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. xe2x80x9cCompatiblexe2x80x9d may be defined as xe2x80x9ccapable of forming a chemically or biochemically stable system.xe2x80x9d The formulations may also include, for example, excipients, fillers, binders, diluents, disintegrants, lubricants, colorants, flavoring agents, and wetting agents. Formulations include those suitable for oral, rectal, nasal, topical (including transdermal, buccal, mucosal, and sublingual), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, and intradermal) administration. The formulations may be prepared by any methods well known in the art of pharmacy, for example, using methods such as those described in Gennaro et al., Remington""s Pharmaceutical Sciences (18th ed., Mack Publishing Company, 1990, see especially Part 8: Pharmaceutical Preparations and their Manufacture).
The forms for administration of mirtazapine may also vary greatly. Formulations suitable for oral administration may be presented as discrete units such as pills, tablets, or capsules, each containing a predetermined amount of active ingredient; as a powder or granules; as a solution or suspension. The active ingredient may also be present as a bolus or paste, or may be contained within liposomes. Formulations for rectal administration may be presented as a suppository or enema. For parenteral administration, suitable formulations include aqueous and nonaqueous sterile injection. The formulations may be presented in unit-dose or multi-dose containers, for example, sealed vials and ampoules, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water, prior to use. Formulations suitable for administration by nasal inhalation include fine dusts or mists which may be generated by means of metered dose pressurized aerosols, nebulizers or insufflators.
Mirtazapine may be prepared using the methods described in U.S. Pat. No. 4,062,848, the disclosure of which has been incorporated by reference above. A suitable pharmaceutical formulation for use in the present invention is REMERON(copyright) brand mirtazapine tablets. REMERON(copyright) is supplied for oral administration as scored, film-coated tablets containing either 15 or 30 mg of mirtazapine and unscored, film-coated tablets containing 45 mg of mirtazapine. Each tablet also contains corn starch, hydroxypropyl cellulose, magnesium stearate, colloidal silicon dioxide, lactose, and other inactive ingredients. Formulating suitable mirtazapine-containing tablets is thus well known to those skilled in the art.
In another embodiment, mirtazapine may be formulated in the form of a solid pharmaceutical dosage form adapted for oral administration, e.g., as taught in U.S. Pat. No. 5,178,878. As explained therein, such a dosage form includes a mixture incorporating at least one water and/or saliva activated effervescent disintegration agent and also microparticles which contain, inter alia, the pharmaceutical ingredient, in this case mirtazapine. This mixture may be used in the form of a tablet which substantially and completely disintegrates upon exposure to water and/or saliva, so that when the tablet is taken orally, the effervescent disintegration agent aids in rapid dissolution of the tablet and permits release of the microparticles, and swallowing of the microparticles, before the pharmaceutical ingredient is even release therefrom.
The invention is further illustrated, but not intended to be limited by, the following example: